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Background: The present investigation provides a thorough analysis of adverse drug reactions (ADRs) reported in the Database of the Spanish Pharmacovigilance System (FEDRA) for biologic medications primarily indicated for severe refractory asthma, including omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab. Our main objective was to identify ADRs not documented in the drugs' Technical Sheets (summary of product characteristics, SmPC), potentially indicating unrecognized risks meriting pharmacovigilance attention. Methods: Data spanning from each drug's market introduction until 22 January 2024, were analyzed, sourced from direct submissions to the Spanish Pharmacovigilance System, industry communications, and literature reviews. We evaluated notifications impartially to ensure a comprehensive review of all the ADRs associated with these medications. Results: This investigation underlines the critical role of post-marketing surveillance in enhancing patient safety. It emphasizes the necessity for healthcare professionals to report ADRs comprehensively to foster a robust pharmacovigilance system. Furthermore, the study highlights gaps between the reported ADRs and the information provided in SmPCs, signaling potential areas for improvement in drug safety monitoring and regulatory oversight. Conclusions: Finally, these findings may contribute to informed decision making in clinical practice and regulatory policy, ultimately advancing patient care and safety in the management of severe uncontrolled asthma.
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Food allergies have increased significantly in recent decades, with shellfish being a leading cause of food allergy and anaphylaxis worldwide, affecting both children and adults. The prevalence of shellfish allergies is estimated to be approximately 0.5-2.5% of the general population, varying significantly by geographical location, age, and consumption habits. Although mollusk consumption has risen, the prevalence of mollusk allergies remains unknown. While extensive research has focused on crustacean allergies, mollusk allergies, particularly those related to gastropods, have received comparatively less attention. Clinical manifestations of shellfish allergy range from localized symptoms to life-threatening systemic reactions, such as anaphylaxis. Notably, severe bronchospasm is a predominant clinical feature in cases involving gastropods. Several allergens have been identified in mollusks, including paramyosin, tropomyosin, and sarcoplasmic calcium-binding protein. In gastropods, documented allergens include tropomyosin, paramyosin, the heavy chain of myosin, and Der p 4 amylase. Diagnosis typically involves a thorough clinical history, skin testing, in vitro quantification of immunoglobulin (Ig) E, and confirmation through an oral challenge, although the latter is reserved for selected cases. This narrative review highlights the limited research on gastropod allergy. It provides a comprehensive list of purified and recombinant allergens and discusses the applications of component-resolved diagnosis as well as current therapeutic developments.
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In Spain, specialist outpatient care traditionally relied on in-person consultations at public hospitals, leading to long wait times and limited clinical analysis in appointment assignments. However, the emergence of Information and Communication Technologies (ICTs) has transformed patient care, creating a seamless healthcare ecosystem. At the Allergy Department, we aimed to share our experience in transitioning form a traditional linear model of patient flow across different healthcare levels to the implementation of a digital ecosystem. By telemedicine, we can prioritize individuals based on clinical relevance, promptly and efficiently addressing potentially life-threatening conditions such as severe uncontrolled asthma or hymenoptera venom anaphylaxis. Furthermore, our adoption of telephone consultations has markedly reduced the need for in-person hospital visits, while issues with unstable patients are swiftly addressed via WhatsApp. This innovative approach not only enhances efficiency but also facilitates the dissemination of personalized medical information through various channels, contributing to public awareness and education, particularly regarding allergies. Concerns related to confidentiality, data privacy, and the necessity for informed consent must thoroughly be addressed. Also, to ensure the success of ICT integration, it is imperative to focus on the quality of educational information, its efficient dissemination, and anticipate potential unforeseen consequences. Sharing experiences across diverse health frameworks and medical specialties becomes crucial in refining these processes, drawing insights from the collective experiences of others. This collaborative effort aims to contribute to the ongoing development of a more effective and sustainable healthcare system.
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Allergen immunotherapy (AIT) with aeroallergens is the only disease-modifying treatment for patients with different allergic conditions. Despite the effectiveness of AIT having been proven in both randomized controlled trials and real-world studies, it remains underused in less than 10% of subjects with allergic rhinitis (AR) and/or asthma (A). We aimed to determine the current eligibility for house dust mite (HDM) AIT by means of a precision allergy molecular diagnosis (PAMD@) model in a selected cohort of youngsters with different allergic phenotypes according to the available evidence. A complex response to both HDM and storage mite allergens was depicted regardless of the subjects' basal atopic condition. No solely specific IgE-binding responses to Der p 1, Der p 2, and/or Der p 23 were found in the studied cohort. Despite the patients with A and atopic dermatitis showing significantly higher serum titers to six mite allergens than subjects with AR, no specific molecular profile was regarded as disease specific. Given the increasing complexity of specific IgE responses to the local prevailing aeroallergens, the identification and presence of such molecules are needed in commercially available AIT in the era of precision medicine.
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Climate change and exposure to environmental pollutants play a key role in the onset and aggravation of allergic diseases. As different climate-dependent patterns of molecular immunoglobulin E (IgE) reactivity have been regionally described, we sought to investigate the evolving allergen exposome in distinctive allergic phenotypes and subtropical weather conditions through a Precision Allergy Molecular Diagnosis (PAMD@) model. Concurrent sensitization to several house dust mites (HDM) and storage mite molecules were broadly dominant in the investigated cohort, followed by the major cat allergen Fel d 1, and regardless of the basal allergic disease. Although a complex repertoire of allergens was recognized, a steadily increasing number of IgE binding molecules was associated with the complexity of the underlying atopic disease. Besides the highly prevalent IgE responses to major HDM allergens, Der p 21, Der p 5, and Der p 7 also showed up as serodominant molecules, especially in subjects bothered by asthma and atopic dermatitis. The accurate characterization of the external exposome at the molecular level and their putative role as clinically relevant allergens is essential to elucidate the phenotypic diversity of atopic disease in terms of personalized diagnosis and therapy.
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Dermatite Atópica , Expossoma , Hipersensibilidade , Humanos , Alérgenos , Dermatite Atópica/diagnóstico , Fenótipo , Imunoglobulina E , Antígenos de DermatophagoidesRESUMO
BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4
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Antiasmáticos , Asma , Humanos , Antiasmáticos/uso terapêutico , Estudo de Associação Genômica Ampla , NF-kappa B/genética , Administração por Inalação , Asma/tratamento farmacológico , Asma/genética , Corticosteroides/uso terapêutico , Genética Humana , Citidina Desaminase , Antígenos de Histocompatibilidade Menor , Proteínas de Transporte/genéticaRESUMO
INTRODUCTION AND OBJECTIVES: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. MATERIALS AND METHODS: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.
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BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.
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Asma , Hispânico ou Latino , Adolescente , Humanos , Asma/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Criança , Americanos MexicanosRESUMO
BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.
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Antiasmáticos , Asma , Microbiota , Humanos , Antiasmáticos/uso terapêutico , RNA Ribossômico 16S , Administração por Inalação , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , BiomarcadoresRESUMO
Severe asthma (SA) is categorized into multiple overlapping phenotypes and clinical characteristics driven by complex mechanistic inflammatory pathways. Mepolizumab is a human monoclonal antibody effectively targeting interleukin-5 in severe eosinophilic asthma. However, the eligibility of biologics in coincident SA phenotypes is still unclear. We assessed the efficacy and safety of mepolizumab in real-life patients with the overlapping T2-high SA endotype. This was a phase IV, single-centre observational cohort study including patients with severe refractory T2-high asthma in treatment with mepolizumab. After 12 months of treatment with mepolizumab, significant improvements (p < 0.0001) in asthma control and lung function were recorded. Rates of clinically significant annual asthma exacerbation were also decreased by 71.22% after 52-week therapy with mepolizumab (p < 0.001) associated with a reduction in the mean daily dose of oral corticosteroids. Two patients (3.27%) had to discontinue mepolizumab due to musculoskeletal disorders with no severe safety issues reported. The use of mepolizumab as an add-on therapy in routine clinical practice was safely associated with significant clinical and functional in the overlapping eosinophilic-and-allergic SA phenotype. The current data should support clinical and therapeutic decision-making in this T2-high SA endotype.
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Background: Atopic dermatitis (AD) is regarded as a chronic systemic disease which is characterized by a robust overexpression of type 2 related cytokines, with increased total IgE levels and a concomitant sensitization to common allergens. Dupilumab, a fully human monoclonal antibody (mAb) to IL-4Rα that inhibits both IL-4 and IL-13 signaling, has previously shown a marked and rapid improvement when treating the moderate-to-severe forms of AD. We sought to evaluate the real-world evidence (RWE) of dupilumab in the modulation of total and specific IgE (sIgE) serum levels to a panel of molecular house dust mites (HDM) and storage mites (SM) allergens in patients with severe AD. Methods: Demographic and clinical data for severe AD adult patients receiving dupilumab treatment (300 mg every 2 weeks) were reviewed. Mean (standard deviations SD) values and percent changes from baseline in total and sIgE to the complete HDM and SM extracts, and 14 individual molecular allergens were measured over 52 weeks. Results: Significant (p < 0.05) changes in mean total IgE levels were observed from baseline to week-52 after treatment with dupilumab. Despite no changes were found in sIgE against the extract of HDM during the 52-week treatment with dupilumab, baseline mean levels from 7 out of 14 individual molecular mite allergens -Der p 1, Der p 2, Der p 5, Der p 7, Der p 21, Der p 23, and Lep d 2- were significantly (p < 0.05) decreased-after 52 weeks of treatment with dupilumab. Conclusions: Dupilumab therapy for 52 weeks resulted in a profound reduction in blood levels of total IgE and allergen-specific IgE to both HDM and SM at the molecular level in adults with severe AD under RWE conditions. The potential benefits of these concomitant immunomodulatory effects after treatment with dupilumab should be explored to a greater extent.
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Storage mites (SM) may induce allergic respiratory symptoms in sensitized individuals, in both rural and urban settings. The relationship among specific IgE reactions to determined groups of SM allergens in the coincident asthma pheno-endotypes has not yet been investigated. We aimed to study a Precision Allergy Molecular Diagnosis (PAMD@) model to depict the SM molecular profile in individuals presenting with Type-2 inflammation, in two different (moderate and severe) asthma phenotypes. A customized PAMD@ panel, including SM allergens and their concurrent protein allergenic characterization was investigated. Mite group 2 allergens were most frequently recognized, including Lep d 2 (83.45%), followed by Gly d 2 (69.17%) and Tyr p 2 (47,37%), in 133/164 asthmatic subjects. Blo t 5 and Blo t 21 exhibited significant higher titres in both asthma groups. Although relevant mite group 2 allergens cross-reactivity is suggested, individualized sensitization patterns were relevantly identified. The present PAMD@ panel confirmed the dominance of mite group 2 allergens in moderate-to-severe T2 asthmatics. A broadly heterogeneous molecular repertoire of SM allergens was found in all subjects, regardless of their asthma severity. Blomia tropicalis deserves special attention in certain territories, as diagnostic and/or therapeutic approaches merely based on Pyroglyphidae mites may be insufficient.
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Acaridae , Asma , Hipersensibilidade , Ácaros , Alérgenos/genética , Animais , Antígenos de Dermatophagoides , Asma/diagnóstico , Humanos , Hipersensibilidade/diagnóstico , Imunoglobulina E/genética , Fenótipo , PyroglyphidaeAssuntos
Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Indóis/efeitos adversos , Moduladores de Transporte de Membrana/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Quinolinas/efeitos adversos , Síndrome de Stevens-Johnson/etiologia , Adulto , Combinação de Medicamentos , Humanos , Masculino , Síndrome de Stevens-Johnson/diagnósticoRESUMO
Atopic dermatitis (AD) endotyping might be important for developing personalized diagnostic and therapeutic strategies to the different phenotypes. The current study investigated the IgE molecular profile to Dermatophagoides pteronyssinus (D. pteronyssinus) in a subset of patients afflicted with varying severity stages of atopic dermatitis in a subtropical region subjected to a high perennial house dust mite (HDM) exposure. We selected patients showing a clinically relevant sensitization to HDM with mild-to-moderate and severe AD according to their basal Severity Scoring Atopic Dermatitis (SCORAD) index. Skin prick test (SPT) with standardized mite extracts, as well as a Precision Allergy Molecular Diagnosis (PAMD@) panel including nine different D. pteronyssinus allergens and the related protein allergenic characterization, were assessed in all serum samples. A total of 80 European American AD patients with the marked T2 endotype confirmed their eligibility for the study. Major allergens (Der p 23, Der p 2, and Der p 1) were present in more than 86% of all subjects, with mid-tier allergens (Der p 5, Der p 7, and Der p 21) reaching up to 65%. A serodominant role for Der p 11 could not be quantitatively confirmed in the present cohort. The proposed component resolved diagnosis (CRD) panel appeared to be sufficient to obtain a precise D. pteronyssinus molecular diagnosis in AD patients subjected to a climate-dependent high-mite allergen exposure. The raised seroprevalence of IgE response to Der p 23 confirmed this constituent as a major D. pteronyssinus allergen in severe stages of atopic dermatitis. A clinically driven molecular approach appears to be essential to frame a more precise diagnosis and therapy of this heterogeneous allergic condition.
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BACKGROUND: Monitoring cellular immune responses elicited in vaccinated individuals is highly complicated. METHODS: 28 individuals participated during the vaccination process with 12 BNT162b2 mRNA (Pfizer) vaccine. Specific anti-RBD IgG using a classic ELISA was performed in days 10 and 20 (after one dose of the vaccine) and on day 35 (after two vaccine doses) in serum samples of all participants. In parallel, DTH (delayed-type hypersensitivity) Skin Test using S protein was performed before (11/28) and after two doses (28/28) of the vaccine. RESULTS: 6/28 individuals were considered positive for the specific anti-RBD IgG positive at day 10, whereas all 28 individuals were positive at day 20. Moreover, 28/28 individuals increased the OD ratios at day 36 (2 doses). DTH cutaneous test was performed on 11/28 participants at day 20 (1 dose) showing 8/11 a positive reaction at 12 h. DTH of all participants was performed on day 36 (2 doses), showing 28/28 positive reactions at 12 h. CONCLUSION: This report describes the first publication of the results obtained using an in vivo method, the classical DTH response to the Spike protein to assess T-cell immune responses in vaccinated individuals. This affordable and simple test would help to answer basic immunogenicity questions on large-scale population vaccine studies.